Allodynia – What Is It, Symptoms, Causes, and Connection to CRPS

In this video, Dr. K discusses desensitizing the nervous system to help patients with allodynia. She will showcase some of the seemingly unusual methods Dr. Katinka van der Merwe uses to help patients with CRPS

Most people suffering from Complex Regional Pain Syndrome suffer from a strange and debilitating symptom called allodynia. What is allodynia?  Allodynia causes you to be extremely sensitive to touch. When one suffers from allodynia, activities that aren’t usually painful can result in severe pain. For example, wearing clothes (even the softest of fabrics), sleeping underneath a sheet, having the wind or air conditioning blow on your skin, or being lightly brushed by something or someone. The lightest touch can become your worst enemy.  This defies logic and most often does not make sense to the general public, adding to your misery.

What Causes Allodynia? 

So, what is this strange pain? What causes allodynia? Traditionally, we think that nerves are involved with pain. While this is true, the nervous system is not the only player. The immune system is also involved (Latremoliere & Woolf, 2009; Kuner, 2010; Gold & Gebhart, 2010; grace, Hutchinson, Maier & Watkins 2014, Chamessian & Zhang, 2016; Clark & Malcangio 2015).

While CRPS research is scant (thanks to it being classified as a “rare disease”, the following hypothesis, in my opinion, offers the most plausible explanation of allodynia. It involves two major systems in the body: the nervous system, and the immune system. Bear with me as I explain an incredibly complicated cascade of events as simple as possible. The major players in the development of allodynia must first be understood.


What Are Cytokines?

Cytokines are very important small proteins that are crucial in controlling the growth and activity of certain immune and blood cells. When released, they signal the immune system to do its job. Cytokines affect the growth of all blood cells and other cells that help the body’s immune and inflammation responses. They are crucial players in the body’s immune response to any invaders (or perceived invaders; an important distinction.)

It has been shown that certain cytokines are involved in not only the initiation but also the persistence of pathologic (abnormal) pain by directly activating nociceptive sensory neurons. Nociceptors are the nerves that sense and respond to parts of the body that are damaged. A good example of nociceptive pain is the pain experienced after burning.

Certain inflammatory cytokines are also involved in nerve injuries and inflammation-induced central sensitization. Central sensitization can be defined as a state in which the central nervous system amplifies normal sensory input and interprets it as pain.

Certain inflammatory cytokines in the dorsal root ganglion (or DRG, a collection of afferent sensory nerves that exist just outside of the spinal cord) are known to be associated with abnormal pain behaviors and spontaneous activity from injured nerve fibers or neurons.  (Afferent means traveling up to the brain, rather than away from the brain to the body). After a peripheral nerve injury (peripheral meaning “away from the center of the body”, immune cells that gather around the injured nerve(s) secrete cytokines. As a result, inflammatory irritation of the dorsal root ganglion (DRG) not only increases pro-inflammatory cytokines but also decreases anti-inflammatory cytokines. There is a lot of evidence that certain pro-inflammatory cytokines, as a result, are involved in the process of pathological (abnormal) pain.


What Is Sympathetic Sprouting?

Nerve sprouting is the process whereby nerve cells generate additional branches (outgrowths) to establish new synapses or to alter the strength of existing synapses, most often after nerve injury. A synapse is a small gap between two neurons, where nerve impulses are relayed by a neurotransmitter from the axon of a presynaptic (sending) neuron to the dendrite of a postsynaptic (receiving) neuron. It is referred to as the synaptic cleft or synaptic gap. In the nervous system, a synapse permits a nerve cell (or neuron) to pass a chemical or electrical signal to another neuron. In animal models of pathological pain, abnormal sprouting of sympathetic fibers around large- and medium-size sensory neurons has been observed in dorsal root ganglia (DRG). Pro-inflammatory cytokines play a facilitating role in sympathetic sprouting induced by nerve injury, and its effect on pain behavior is indirectly mediated through sympathetic sprouting in the dorsal root ganglia (DRG).

Following peripheral nerve injury, sympathetic efferent fibers extensively sprout into both the DRG and spinal nerves. Sprouting fibers sometimes form distinctive basketlike webs (called sympathetic “baskets”), wrapping around DRG nerves. Pain induced by localized inflammation of the DRG or mechanical compression of the DRG in the absence of nerve injury can also be accompanied by sympathetic sprouting. Nerve sprouting usually causes proliferation of sensory nerve (in other words, instead of a nerve here and there, you now have a dense network of nerves).


What Is Sympathetically Maintained Pain (SMP)?

The specific pain accompanied by hypersensitivity that CRPS patients suffer from is called sympathetically maintained pain (SMP). SMP is the result of efferent (away from the brain to the peripheral nerves) noradrenergic pain. Noradrenergic means that the nerves use norepinephrine, a neurotransmitter released by the sympathetic nervous system. Keep in mind that CRPS patients suffer from sympathetic dominance. In a small percentage of cases, SMP will respond well in the early stages to a nerve block, which is why CRPS patients are told that it is crucial to get treatment early on.

In addition, the evil monster known as SMP is created when there is abnormally enhanced communication between the sympathetic nervous system and the sensory nervous system. This enhanced communication may happen either in the central or peripheral nervous system. Pain induced by localized inflammation of the DRG or mechanical compression of the DRG in the absence of nerve injury can also be accompanied by sympathetic sprouting in the DRG.

 When an inflammatory response occurs anywhere in the body, the brain is alerted to the presence of inflammation-associated molecules such as cytokines circulating in the blood. While the research of neuroimmune pathways is still in its infancy, there are currently three different pathways through which this alert can occur. Immune proteins such as cytokines will

1) By being detected by receptors in the afferent (sensory) vagus nerve

2) By being actively transported across the blood-brain barrier (BBB). The Blood-Brain Barrier is a collection of endothelial cells, ideally functioning to act as a gatekeeper to keep dangerous chemicals and substances out of the brain.

3) By being passively diffused through the BBB if present in high enough concentrations.


Cytokine Signaling Gone Wrong

Cytokine signaling from the peripheral side of the BBB triggers exactly the same glial activation and cytokine release inside the brain. Even the smallest infection or source of inflammation may trigger this response. This happens despite the BBB. Glial cells are a class of cells that function where the nervous and immune systems overlap, one affecting the other. The primary glial cells of the central nervous systems are microglia, which are macrophages that are capable of detecting proinflammatory cytokines. When these cells detect pro-inflammatory chemicals and substances such as cytokines, they, in turn, produce their own chemicals and proinflammatory cytokines. This results in the surrounding glia becoming “excited” or activated. It’s now known that injury and environmental stressors can cause the microglial cells to become ‘stuck’ in a hyperexcited defensive mode, like soldiers always ready to fight. Once in this state, the smallest stimuli can cause the glial cells to begin releasing proinflammatory cytokines resulting in abnormal pain response.


 Toll-like Receptors (TLRs)

Toll-like receptors (TLRs) are an important family of receptors that form the first line of the defense system against microbes. They are able to recognize both pathogens and chemicals released from damaged tissues and dying cells. These receptors are able to recognize abnormal patterns associated with the immune response. TLRs form a vital bridge or link between the body’s immune and nervous systems. TLRs initiate the inflammatory response in an effort to protect the body. At least one study showed that mice developed allodynia as a response to up-regulation of activation transcription factor 3 (ATF3) in the dorsal root ganglion (DRG). ATF3 is activated by TLRs (Park, Stokes, Corr & Yaksh, 2014)

Accumulating evidence now exists that shows that TLR activation and its effect on the glial cells and sensory neurons can affect the way humans process pain and lead to states of unresolved and exaggerated pain. Some scientists have been able to reverse nerve pain in rats by administering TLR inhibitors (Lacagnina, Watkins & Grace, 2018).

Keep in mind, while infections are the possible culprit, they are not the only culprit. ANY inflammatory response may trigger this cascade of events. That means that the culprit could also be an allergen, injury, or chemical. The TLR response to environmental factors indicates that damage, not infection, is usually the primary culprit.  Of course, any infection could cause resulting inflammation and damage, but infection is not necessary for  TLRs to respond to.

While all of this may seem complicated, the main takeaway I want you to get from this is that the smallest injury or infection may cause the horrible condition known as allodynia and that the immune system is just as involved as the nervous system. Your body is doing the right thing and fighting for you valiantly, it’s just doing it at the wrong time, and too excessively.

When treating this pain, I believe that outdated methods such as desensitization does not get to the root of the problem. I often say if someone doesn’t like being slapped, slapping them 1000 times so that they can get used to it is not a workable solution. In order to permanently heal allodynia, the body needs to be supported from within so that the nervous system may heal and the inflammation is calmed, resulting in this cascade of events to be reversed.

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CRPS treatment clinic patient Bria with dr.katinka